Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

Nature (Impact Factor: 41.46). 07/2014; 513(7516). DOI: 10.1038/nature13528
Source: PubMed


Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

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Available from: Lawrence Kazak, Jul 28, 2014
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    • "For instance, blockade of IL6 or BAT denervation significantly impaired cachexia-associated beige adipocyte biogenesis (Petruzzelli et al., 2014). In addition , Parathyroid hormone-related protein (PTHrP) derived from the Lewis lung carcinoma potently promotes beige adipocyte biogenesis (Kir et al., 2014). High level of serum PTHrP is associated with lean body mass in cachectic mice and humans. "
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    Cell metabolism 10/2015; 22(4):546-559. DOI:10.1016/j.cmet.2015.09.007 · 17.57 Impact Factor
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    • "A recent study has found that the thermogenic program is activated in fat cells treated with the conditioned medium from Lewis lung carcinoma (LLC) cells, a well-characterized model of cachexia (Kir et al. 2014). Global gene expression analysis of LLC cells identified parathyroid hormone-related protein (PTHrP) as regulating the activation of thermogenesis, probably through the cAMP/PKA pathway (Kir et al. 2014). This discovery has begun to provide mechanistic insights into the etiology of the development of cachexia and further studies may suggest treatments that can prevent tissue wasting during disease. "
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    • "In fact, recent advances in molecular and cell biology have provided a high spectrum of novel drug targets, such as the ActRIIB pathway [100], the adipose triglyceride lipase or hormone-sensitive lipase [25], the HMGB1 protein [62] and the tumor-derived parathyroidhormone-related protein [52]. However, the current lack of success for a single therapy indicates that cancer cachexia intervention may include different approaches, including non-pharmacological strategies, such as AET ([32]; [5] [90]). "
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    ABSTRACT: Aerobic exercise training (AET) induces several skeletal muscle changes, improving aerobic exercise capacity and health. Conversely, to the positive effects of AET, the cachexia syndrome is characterized by skeletal muscle wasting. Cachexia is a multifactorial disorder that occurs and is associated with other chronic diseases such as heart failure and cancer. In these diseases, an overactivation of ubiquitin-proteasome and autophagy systems associated with a reduction in protein synthesis culminates in severe skeletal muscle wasting and, in the last instance, patient's death. In contrast, AET may recycle and enhance many protein expression and enzyme activities, counteracting metabolism impairment and muscle atrophy. Therefore, the aim of the current review was to discuss the supposed therapeutic effects of AET on skeletal muscle wasting in both cardiac and cancer cachexia. Copyright © 2014. Published by Elsevier Inc.
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